This program project grant is a new proposal to develop vaccines by the Steinman-Nussenzweig-Ravetch laboratories. It is focused on investigating the hypothesis that antigens delivered directly to dendritic cells in conjunction with a maturation stimulus will enhance immunity and elicit productive immune responses to vaccine antigens. The program will exploit the principles of dendritic cell biology and immunology more broadly to design and develop vaccines, including phase I studies in humans. Specific aims are: 1) Develop DNA vaccines that incorporate dendritic cell targeting strategies and test the vaccines in humans 2) Regulate FcR signaling on DC subsets as a means of controlling DC maturation and the generation of antigen-specific immnunity. 3) Identify antigens that induce broadly neutralizing anti-HIV-1 antibodies by cloning such antibodies from single B cells from rare individuals that control their HIV-I infection and controls that do not All of the projects proposed in this program will address these three areas using the complementary strategies outlined in the proposal. The information generated by each project will allow the group as a whole to adjust its strategy accordingly. Thus, the strength of the proposed program project lies in the expertise of the investigators, the proven record of their collaborations with other members of the program, and the close relationship each project has to the overall goals of the program.